Method for the preparation of 6α-fluoro corticosteroids

Abstract

A method for producing a 6α-fluorinated corticosteroid or derivative thereof by reacting a 17-hydroxy-21-ester epoxide of Formula II with a stereoselective fluorinating agent to stereoselectively form a 21-ester-17-hydroxy 6α-fluorinated compound of Formula VII R 1 can be OC(O)—R d ; R 4 can be C(O)—R d ; R 3 can be H or R d . Each R d may be the same or different and is independently selected from (C 1-4 )alkyl, aryl and heteroaryl. The dashed line can be a single or a double bond. R 4 may be, for example, acetyl; R 3 may be, for example, alpha or beta methyl; R 1 may be, for example, acetate or propionate. The stereoselective fluorinating agent used in the reaction may be, for example, a fluoropyridinium or fluoroquinuclidium compound, for example, Selectfluor®.

1. A method of preparing a 6α-fluorinated corticosteroid, comprising the steps of:
 (a) reacting a 21-ester, 17-hydroxy epoxide of Formula XXV 
 
       
         
           
           
               
               
           
         
          with a stereo selective fluorinating agent to stereo selectively form a 21-ester, 17-hydroxy, 6α-fluorinated compound of Formula XXVI; 
       
       
         
           
           
               
               
           
         
         (b) reacting the 21-ester, 17-hydroxy, 6α-fluorinated compound of Formula XXVI with hydrofluoric acid to form a 21-ester, 11,17-dihydroxy, 6α,9α-difluorinated compound of Formula XXVII; and 
       
       
         
           
           
               
               
           
         
         (c) reacting the 21-ester, 11,17-dihydroxy, 6α,9α-difluorinated compound of Formula XXVII with a weak base to form a 11,17,21-trihydroxy, 6α,9α-difluorinated compound of Formula XXVIII, 
       
       
         
           
           
               
               
           
         
          wherein n=1 or 2, and the stereoselective fluorinating agent is selected from the group consisting of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), 1-fluoropyridinium triflate, 1-fluoropyridinium tetrafluoroborate, and 1-fluoropyridinium pyridine heptafluorodiborate. 
       
     
     
       2. The method of  claim 1 , wherein step (a) is conducted in acetonitrile. 
     
     
       3. The method of  claim 1 , wherein the compound of Formula XXVIII is diflorasone. 
     
     
       4. The method of  claim 1 , wherein the compound of Formula XXVIII is flumethasone. 
     
     
       5. The method of  claim 3 , further comprising the steps of:
 (d) reacting the 11,17,21-trihydroxy, 6α,9α-fluorinated compound of Formula XXVIII with trimethyl orthoacetate to form a 17-propionate ester; 
 (e) reacting the 17-propionate ester with mesyl chloride to form a 21-mesylate; and 
 (f) reacting the 21-mesylate with a chloride containing salt to form halobetasol propionate. 
 
     
     
       6. A method of preparing diflorasone, comprising the steps of:
 (a) reacting an epoxide of Formula XX 
 
       
         
           
           
               
               
           
         
          with a stereoselective fluorinating agent to stereoselectively form a compound of Formula XXI; and 
       
       
         
           
           
               
               
           
         
         (b) converting the compound of Formula XXI to diflorasone, wherein R 1  is OC(O)—R d , R 4  is C(O)—R d , and each R d  may be the same or different and is independently selected from the group consisting of (C 1-4 )alkyl, aryl and heteroaryl. 
       
     
     
       7. The method of  claim 6 , wherein R 1  is acetate, R 4  is acetyl, the stereoselective fluorinating agent is 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) and step (b) further comprises the steps of:
 (i) reacting the compound of Formula XXI with HF to form a 9α-fluorinated and epoxide ring-opened ester; and 
 (ii) hydrolyzing the 9α-fluorinated and epoxide ring-opened ester using a weak base. 
 
     
     
       8. A method of preparing halobetasol propionate, comprising the steps of:
 (a) reacting an epoxide of Formula XX 
 
       
         
           
           
               
               
           
         
          with a stereoselective fluorinating agent to stereoselectively form a compound of Formula XXI; and 
       
       
         
           
           
               
               
           
         
         (b) converting the compound of Formula XXI to halobetasol propionate, wherein R 1  is OC(O)—R d , R 4  C(O)—R d , and each R d  may be the same or different and is independently selected from the group consisting of (C 1-4 )alkyl, aryl and heteroaryl.